Prostaglandin D2 (abbreviated as PGD2) has been known as one of metabolites produced via an arachidonic acid cascade and is considered to be one of chemical mediators participating in allergic diseases such as allergic rhinitis, bronchial asthma and allergic conjunctivitis. It has been known that PGD2 is mainly produced in and released from mast cells and that the PGD2 released shows contraction of bronchus, promotion of vascular permeability, dilation or contraction of blood vessels, promotion of mucus secretion and inhibition of platelet aggregation. It has been also reported that PGD2 induces bronchoconstriction and nasal obstruction in vivo as well and increased amounts of production of PGD2 in pathological lesion of patients suffering from systemic mastocytosis, allergic rhinitis, bronchial asthma, atopic dermatitis, urticaria, etc. (N. Engl. J. Med. 1989; 303: 1400-4, Am. Rev. Respir. Dis. 1983; 128: 597-602, J. Allergy Clin. Immunol. 1991; 88: 33-42, Arch. Otolaryngol. Head Neck Surg. 1987; 113: 179-83, J. Allergy Clin. Immunol. 1988; 82: 869-77, J. Immunol. 1991; 146: 671-6, J. Allergy Clin. Immunol. 1989; 83: 905-12, N. Eng. J. Med. 1986; 315: 800-4, Am. Rev. Respir. Dis. 1990; 142, 126-32, J. Allergy Clin. Immunol. 1991; 87: 540-8, J. Allergy Clin. Immunol 1986; 78: 458-61). PGD2 has been also reported to participate in nerve activity, particularly in sleeping, hormone secretion and pain. Furthermore, it has been also reported that it participates in platelet aggregation, glycogen metabolism and adjustment of intraocular pressure.
PGD2 exerts its biological activity via binding to a DP receptor, which is one of PGD2 receptors. Since DP receptor antagonists bind to its receptor and show antagonistic activity, DP receptor antagonists have been believed to be useful for prevention and/or treatment of diseases such as allergic diseases (e.g., allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma and food allergy), systemic mastocytosis, disorders accompanied by systemic mast cell activation, anaphylactic shock, bronchoconstriction, urticaria, eczema, acne, allergic bronchial pulmonary aspergillosis, sinusitis, migraine, nasal polypus, anaphylactic vasculitis, eosinophilic syndrome, contact dermatitis, diseases accompanied by itch (e.g., atopic dermatitis, urticaria, allergic conjunctivitis, allergic rhinitis and contact dermatitis), diseases (e.g., cataract, retinal detachment, inflammation, infection and sleeping disorders) which are generated secondarily as a result of behavior accompanied by itch (e.g., scratching and beating), inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion injury, cerebrovascular accident, autoimmune disease, traumatic brain disorder, hepatopathy, graft rejection, chronic rheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, etc. It also participates in sleep and platelet aggregation and is believed to be useful for those diseases as well.
For example, in the specification of WO 86/05779, compounds represented by formula (T) are useful as antagonists for SRS-A (slow reacting substance of anaphylaxis):
(in the formula, AT is a hydrogen atom, phenyl or phenoxy; nT is an integer from 3 to 10; R1T is a hydrogen atom or a lower alkoxy; X1T is —CH2—Y1T— (in the group, Y1T is —O—, —S— or —NH—), —CO—Y2T— (in the group, Y2T is —O—, —S— or —NH—), etc.;
is a group represented by the formula
etc.; R2T is a hydrogen atom, a halogen atom, nitro, hydroxyl, lower alkoxy, cyano, lower alkyl, lower alkoxy lower alkyl, halo lower alkyl or a group represented by —NR4TR5T—, etc.;
X2T is a formula —Y3T-Y4T— (in the group, Y3T is a single bond, —O—, —S— or —NH— and Y4T is a C1-6 alkylene which may be interrupted by sulfur atom), etc.; and
DT is carboxyl or a lower alkoxycarbonyl and the like).
In prostaglandin receptors, there are many receptors including subtypes and each of them has a different pharmacological action. Now, if novel compounds which specifically binds to a DP receptor and binds weakly to other prostaglandin receptors are able to be found, they can be pharmaceuticals having little side effect since no other functions are not exerted. Therefore, there has been a demand for finding such pharmaceuticals.